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The 23andMe Personal Genome Service (PGS) uses qualitative genotyping to detect select clinically relevant variants in genomic DNA isolated from human saliva collected from individuals ≥18 years with the Oragene Dx model OGD500.001 for the purpose of reporting and interpreting genetic health risks, including the 23andMe PGS Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants).

The 23andMe Personal Genome Service (PGS) Risk Report for BRCA1/BRCA2 (Selected Variants) is indicated for the reporting of the following 44 variants in the BRCA1 and BRCA2 genes.

BRCA1: c.68 69del, c.213-11T>G, c.427G>T, c.815 824dup, c.1556del, c.1687C>T, c.1961del, c.2681 2682del, c.2864C>A, c.3481 3491del, c.3598C>T, c.3627dup, c.3756 3759del, c.3770 3771del, c.4035del, c.4065 4068del.c.4327C>T.c.4357+1G>A.c.4964 4982del.c.4986+6T>G.c.5123C>A.c.5177 5180del.c.5266dup

BRCA2: c.658 659del, c.771 775del, c.2808 2811del, c.2957 2958insG, c.3170 3174del, c.3264dup, c.3545 3546del, c.3847 3848del, c.4471 4474del, c.5542del, c.5576 5579del, c.5682C>G, c.5946del, c.6037A>T, c.6275 6276del, c.7024C>T, c.7480C>T, c.7934del, c.8904del

The report describes if a person's genetic result is associated with an increased risk of developing breast cancer and ovarian cancer and may be associated with an increased risk for prostate cancer, and potentially other cancers. The variants included in this report do not represent the majority of the BRCA1/BRCA2 variants in people of most ethnicities. The test report does not describe a person's overall risk of developing any type of cancer, and the absence of a variant tested does not rule out the presence of other variants that may be cancer-related. This report is for over-the-counter use by adults over the age of 18, and provides genetic information to inform discussions with a healthcare professional. This test is not a substitute for visits to a healthcare provider for recommended screenings or appropriate follow-up and should not be used to determine any treatments.

Customer saliva specimens are self-collected using the Oragene-Dx® Device manufactured by DNA Genotek, Inc. cleared by FDA for use with the PGS device under K141410, which consists of a sealable collection tube containing a stabilizing buffer solution. Once the sample is collected, it is shipped to one of two Clinical Laboratory Improvement Amendments (CLIA) certified laboratories for testing.

DNA is isolated from the saliva and tested in a multiplex assay using a customized genotyping beadchip, reagents and instrumentation manufactured by Illumina.

The raw data is generated using Illumina GenomeStudio software, and then sent to 23andMe for analysis and interpretation. The raw data received is analyzed using 23andMe's proprietary Coregen software, where a genotype is determined for each tested SNP. The results for certain of these SNPs are used to generate personalized reports for the customer that provide information about the detected genotype.

Personalized reports are generated for each user that provide results of the testing performed. These reports tell the user which genetic health risk variant(s) have been detected in their sample and provide information about the disease associated with the variant(s). If no variant was detected, that information is also provided. The personalized reports are designed to present scientific concepts to users in an easy-to-understand format. The reports provide scientifically and clinically valid information about the risks associated with the presence of a particular variant. The reports are designed to help users understand the meaning of their results and any appropriate actions that may be taken based on their results.

Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided FDA 510(k) summary for the 23andMe Personal Genome Service (PGS) Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants):

Acceptance Criteria and Device Performance

1. Table of Acceptance Criteria and Reported Device Performance

2. Sample Size and Data Provenance

• Test Set Sample Size: The exact number of individual samples used for the "Method Comparison" (Accuracy), "Precision" (Reproducibility), and "Minimum DNA Input" studies is not explicitly stated as a numerical count. However, the document mentions that samples were "randomly selected from the 23andMe customer database" and that "all 41 variants were included in this study" for each of these performance tests.
• Data Provenance: The document states that samples were identified from the "23andMe customer database." This implies real-world, likely retrospective, data from individuals who have used 23andMe's services. The country of origin is not explicitly stated for individual samples, but 23andMe is a US-based company, suggesting the data is primarily from the US.

3. Number of Experts and Qualifications for Ground Truth

• This device is a genetic test, and the ground truth for performance testing (accuracy) was established by bidirectional Sanger sequencing, which is a widely accepted and highly accurate method for DNA sequencing.
• The document does not mention the use of human experts (e.g., radiologists) in establishing the ground truth for the analytical validity studies. The "truth" in this context is the confirmed genetic sequence obtained through an orthogonal, highly accurate laboratory method (Sanger sequencing), not human interpretation of images or clinical outcomes.

4. Adjudication Method for the Test Set

• Adjudication methods (e.g., 2+1, 3+1) are typically used in studies involving human interpretation or subjective assessments. Since the performance studies for this genetic test rely on objective laboratory methods (genotyping by the device vs. Sanger sequencing as ground truth), no human adjudication method was needed or applied for the analytical performance tests. The comparison was directly between the device's genotype call and the Sanger sequencing result.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

• No, an MRMC comparative effectiveness study was not done. MRMC studies are relevant for imaging devices or other medical technologies where human readers interpret output, and the goal is to assess how a device affects human performance. This is a direct-to-consumer genetic test (an in vitro diagnostic device) that directly provides genotype information, not an interpretation aid for human experts. Therefore, the concept of human readers improving with AI assistance is not applicable here.

6. Standalone (Algorithm Only) Performance

• Yes, standalone performance was done for the analytical validation. The performance criteria (PPA, NPA, correct genotype calls) were measured for the 23andMe PGS assay (the "algorithm only" in this context of a genetic test) against the ground truth established by Sanger sequencing. The results presented in the acceptance criteria table (e.g., ">99% agreement," "100% correct calls") represent the standalone performance of the device. There isn't a "human-in-the-loop" aspect to the genotyping process itself; the device generates the genotype call automatically.

7. Type of Ground Truth Used

• The ground truth used for the analytical validation test set was bidirectional Sanger sequencing, considered the gold standard for confirming specific DNA sequences and variants.

8. Sample Size for the Training Set

• The document does not specify the sample size for the training set. This is typical for in vitro diagnostic devices like genetic tests where the underlying technology (genotyping method) is well-established. The performance is primarily evaluated through robust analytical validation on a test set, rather than machine learning model training. The device leverages a "customized genotyping beadchip" and "proprietary Coregen software," indicating a deterministic or rule-based approach for genotype calling, or a machine learning model that was developed and validated internally but whose training set details are not part of this 510(k) summary.

9. How Ground Truth for the Training Set Was Established

• Given that the document does not explicitly mention a training set or machine learning model development in the traditional sense, it does not describe how ground truth for a training set was established. For molecular genetic tests, the principles of operation are typically based on molecular biology and chemistry, with performance validated through analytical studies against highly accurate reference methods like Sanger sequencing, rather than training on labeled datasets. If machine learning is involved in the "Coregen software" for genotype determination, the ground truth for any such training would logically have been established through a similar process of comparing assay results to known, validated reference genotypes (e.g., from Sanger sequencing or other established methods).

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